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Prostate cancer is the most common noncutaneous cancer and the second-leading cause of cancer-related death in men in the United States. Prior studies have shown that family history, such as a brother or father with prostate cancer and relatives affected at an early age, is a major risk factor. A growing consensus in the field is that inherited factors for prostate cancer are highly heterogeneous, involving mutations in high penetrance genes that occur in a small number of families, but also alterations in low or moderate penetrance genes that are more common, and which may interact in individuals to promote disease. While a few genes such as BRCA2 and HOXB13 are definitively linked to prostate cancer risk in small patient populations, a greater proportion of prostate cancer risk may be associated with low incidence alleles of intermediate penetrance. While panel testing may be useful in detecting some of these variants, it is difficult to design a panel that adequately captures the rapidly increasingly number of rare variants associated with multiple forms of cancer. With the cost of DNA sequencing rapidly decreasing, analysis of exome and genome data is becoming an alternative approach. However, given the computational complexity of assessing the many rare variants found in every individual, particularly if multiple independent variants may be interacting to produce risk, it is desirable to employ a robust analytic pathway grounded in understanding of the physiological basis of the disease.
In addition to genetic heterogeneity of prostate cancer susceptibility, another common scenario in clinical cancer risk evaluation that impacts the assessment of genetic variants is a “case-only” presentation for genetic testing. This may arise when a patient presents for cancer risk evaluation with small family structure, limited family history information, and limited access to specimens from other affected relatives due to death or other causes. In this situation, the ability to clarify cancer susceptibility of genetic variants using family history or by testing a DNA sample from one or more informative blood relatives (affected or unaffected with cancer) is not possible. Such pedigrees will often be characterized by some prostate cancers, but also other cancers, raising the possibility that some inherited variants may be risk factors for multiple cancer types. In the clinical cancer risk assessment setting, novel pathway-based approaches to identifying at-risk individuals and families are greatly needed.